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Page 12 of 23 Du et al. Soft Sci 2024;4:35 https://dx.doi.org/10.20517/ss.2024.31

Wang et al. have proposed a novel alginate-based pH-responsive hydrogel and explored two major factors
[95]
affecting diabetic wound healing [Figure 3C]. Studies showed that the developed hydrogel contains drugs
and NPs with the potent bactericidal properties of protamine, a major component of the hydrogel,
effectively reducing wound infection caused by bacteria and promoting wound healing. Additionally,
hyaluronic acid, another major component of the hydrogel, can enhance the expression of vascular growth
factor, thereby promoting angiogenesis in skin wounds and further accelerating wound healing.

Liang et al. developed a pH/glucose dual-responsive hydrogel, phenylboronic acid and benzaldehyde
difunctional polyethylene glycol-co-poly(glycerol sebacic acid) (PEGS-PBA-BA)/dihydrocaffeic acid and L-
arginine co-grafting chitosan (CS-DA-LAG) (PC), tailored for the specific needs of diabetic foot wounds
[96]
[Figure 3D]. This hydrogel, utilizing metformin as a model drug, exhibits multiple functions, including
antibacterial activity, hemostasis, and controlled drug release. Compared to other hydrogel dressings, PC
hydrogel offers better adhesion, making it more suitable for human movement. The dual pH/glucose
response enhances wound repair in the low pH and high glycemic environments characteristic of diabetic
wounds. Experimental results demonstrated that this hydrogel could promote diabetic foot healing by
reducing and inhibiting inflammation and enhancing angiogenesis.

The physiological environment of diabetic wounds is complex and variable, making the development of
hydrogel actuators that are more sensitive to environmental changes and respond more rapidly a more
challenging direction for future development.

Periocular disease
Eye infusion is now the conventional treatment for ocular diseases. However, local eye drops suffer from
low patient compliance and reduced bioavailability due to tear drainage . To address these issues,
[112]
hydrogels have been increasingly incorporated into eye drop formulations. In this method, drugs are
encapsulated in a hydrogel that is administered as a liquid at room temperature. Upon contact with body
temperature, the hydrogel undergoes a reversible sol-gel phase transition, prolonging the retention time of
the drug on the eye and enabling sustained release of the therapeutic agent .
[113]

Bellotti et al. proposed a temperture-responsive hydrogel based on poly(N-isopropylacrylamide)
(pNIPAAm) and polyethylene glycol (PEG), incorporating a system containing a degradable microsphere
[97]
made of polylactic acid-hydroxyacetic acid copolymer (PLGA) [Figure 4A]. This hydrogel features lower
LCST and gelation temperatures than other temperature-responsive hydrogels, ensuring rapid gelation after
drug administration. It maintains stability under various conditions, and its drug release profile
demonstrates continuous drug release capacity. This study addresses the issue of high-frequency
administration required for ocular diseases, improving patient compliance. Moreover, it also shows a
promising application in the treatment of various eye diseases.

Iohara et al. proposed a temperture-responsive hydrogel based on a hydrophobically modified polymer/α-
cyclodextrin, demonstrating a reversible solution-gel transition within the physiological temperature
[98]
range [Figure 4B]. Diclofenac sodium was used as the model drug, and the application of hydrophobically
modified hydroxypropyl methylcellulose (HM-HPMC)/α-cyclodextrin (α-CD) significantly enhanced the
ocular absorption of diclofenac sodium. This study tested the efficacy of this thermoresponsive hydrogel in
rabbit eyes. The system leverages the interaction between CD and the hydrophobically modified polymer to
create a thermoresponsive hydrogel, promising numerous applications in the treatment of ocular diseases.